Cardiovascular disease remains a major health problem in the industrialized world and is rapidly gaining a foothold in the Third World. We have learned a great deal about the antecedents of these disorders over the past half century, but that has not markedly reduced the occurrence of these illnesses. Obesity, elevated blood pressure (BP), and increased lipids and glucose are considered important contributing factors to cardiovascular events and have reached epidemic proportions in our society. Increasing evidence is available that links these components, and the term cardiometabolic syndrome has been used by many to describe their coexistence. Both genetic and environmental causes have been implicated. However, these factors are broad descriptors for a variety of abnormalities that may not necessarily be linked. This review will focus on possible relationships between one BP phenotype, salt sensitivity, and the components of the cardiometabolic syndrome.
The salt sensitivity phenotype has been demonstrated to have a variety of etiologies, including genetic susceptibility, myriad physiologic alterations at the level of the vasculature or the kidney, nutritional factors, and other causes.1 While the sources of the phenotype are varied, the definition of the phenomenon is very consistent. Since salt “gluttony” is the standard among most individuals living in industrialized societies, with the consumption of salt averaging 40 times that of biologic requisites, the majority of those who are vulnerable to the BP-raising effects of increased salt intake by virtue of attaining the requisite age, having the genetic background, or the pathophysiologic susceptibility, have already manifested the rise in BP. Increasing the salt intake of such individuals will not generally raise BP further. Thus, salt sensitivity of BP can only be defined by the magnitude of fall in BP following sodium and/or volume depletion.1 Most protocols investigating this phenomenon have, therefore, used a standard salt load to ensure that the subjects are all at the same level of sodium balance and then compared the changes in BP after sodium or volume depletion achieved by a variety of techniques. The maneuvers used for the characterization of BP responsiveness to salt have included dietary manipulation—typically requiring days, weeks, or months of consumption of fixed diets of known sodium content as well as other minerals such as potassium and calcium—or more rapid techniques for sodium and extracellular volume expansion and contraction.1 Careful and multiple measurements of BP are required at the end of each period for accurate assessment of salt responsiveness, with the difference in BP between the high-salt or volume-expanded period and the low-salt and/or volume-depletion phase used to arbitrarily define salt sensitivity and resistance. When the studies are done carefully, they have been found to be reproducible.2,3 In addition, in the few carefully performed studies that have compared two different techniques for the assessment of salt sensitivity in the same individual, they have been congruent.4,5
Many characteristics that differentiate salt-sensitive from salt-resistant subjects have been described. Salt sensitivity is more frequent (≈60%) in hypertensives than in normotensives (≈25%) but can also occur in those with “normal” (i.e. <140/90 mm Hg) BP.6 In the hypertensive population, persons of African-American descent are more likely to be salt-sensitive (≈75%) than those of Caucasian origin (≈50%), but the majority of salt-sensitive hypertensives are Caucasian6. Among the “normotensive” group, no racial differences in the frequency of salt sensitivity have been reported. This suggests that if there is a genetic basis for the racial difference in salt sensitivity of BP, it is only manifested in hypertensives and must have a latency period or a requisite environmental and/or a pathophysiologic cofactor.
Another factor linked to salt sensitivity of BP is age. The magnitude of salt sensitivity increases progressively among hypertensives ranging from 20 years to older than 60, when compared by decades of age.3 This is consistent with the clinical observations that diuretics are effective antihypertensive agents in older hypertensives and/or those of African-American background; both groups in whom salt sensitivity is more prevalent. Among normotensive subjects, salt sensitivity was not observed in groups of individuals younger than 60 years.3 These findings are also consistent with the epidemiologic observations that the age-related rise in BP, that we deem usual, is only seen in societies in which average daily sodium intake is above 50–100 mmol.7 It has also been suggested that salt sensitivity is more prevalent among obese and diabetic subjects; however, these findings have not been confirmed in larger studies.
Many direct and indirect lines of evidence have implicated the kidney in the etiology of salt sensitivity of BP. It has been suggested, on the basis of studies in experimental animals, that a congenital or acquired reduction in glomerular number may contribute to salt-sensitive hypertension, presumably by decreasing glomerular filtration and the ability to excrete a salt load.8 In a situation analogous to that seen in diabetes mellitus, a reduction in glomerular number could initially lead to hyperfiltration of existing glomeruli with subsequent, time-dependent obsolescence of glomeruli and further reduction of glomerular mass. This is certainly an intriguing hypothesis that awaits confirmation in humans.
Many, but not all, salt-sensitive subjects have evidence of renin suppression.6 This cannot be readily identified during usual dietary sodium intake since the relatively high sodium content of typical diets is associated with suppressed renin levels. Thus, sodium and/or volume depletion is required to demonstrate this abnormality of the renin system to respond appropriately to this stimulus. Studies have demonstrated that the higher the renin response to sodium and volume depletion, the smaller the BP response, and vice versa,4 suggesting that a defect in the renal response to sodium and/or volume depletion in appropriately increasing the release of renin to such a challenge exerts a permissive effect in the fall of BP. It has also been suggested that acquired renal injury of a subtle and clinically inapparent nature may be responsible for salt sensitivity of BP.9 Some studies have implicated abnormalities of proximal tubular sodium reabsorption as involved in salt sensitivity of BP.10
Other studies have suggested enhanced sympathetic nervous system activity in response to a salt load as the etiology of salt sensitivity of BR11 However, this has neither been confirmed in larger studies nor does it provide an understandable explanation for the greater fall in BP with sodium and volume depletion since an enhanced sympathetic response would be expected to prevent such a fall. Several other vascular-active factors have been implicated in the mechanism of salt sensitivity of BP, such as components of the eicosanoid system (e.g., 20-hydroxyeicosatetraenoic acid)12 and endothelin. Sodium chloride intake has been suggested as a regulator of endothelin release in one study.13 Presumably, abnormalities of endothelin regulation in response to changes in salt intake could be involved in the variable BP responses.
Obesity, which has long been linked to elevated BP and increased insulin resistance, has been shown to be related to impaired sodium excretion and to a presumably salt-sensitive form of hypertension in adolescents, which can be modified by weight loss.14 A similar finding of abnormal sodium handling was reported in obese Italian men.15 Aldosterone, the principal mineralocorticoid, is involved in sodium and water handling in the distal renal tubule and collecting duct. Elevated levels of this adrenal hormone have also been reported in obese hypertensives.16 Some investigators have suggested that there is an activated renin–angiotensin system in adipose tissue in obese subjects.17,18 Such activation could increase aldosterone production but, after a new steady state is reached, one would expect renin suppression to be observed, which is the typical observation in salt-sensitive hypertensives. However, renin suppression has not been generally described in most obese hypertensives. Another possible explanation for the hyperal-dosteronism associated with obesity is the action of novel mineralocorticoid-releasing factors from adipose tissue.19 In this case, the increased aldosterone production would be associated with increased mineralocorticoid receptor-mediated sodium and water reabsorption, extracellular volume expansion, an increase in BP, and renin suppression—the typical pattern seen in salt-sensitive hypertension. In addition to the effect of factors from the adipocytes directly, the increase in fatty acid oxidation by the liver in obesity could also stimulate aldosterone production.20
How, then, do these observations relate to the cardiometabolic syndrome? Unfortunately, very few longitudinal studies exist to provide a clear understanding of the precise mechanisms involved in the relationships between vascular behavior, BP, insulin sensitivity, renal function, visceral adipose tissue physiology, and the actions of myriad circulating factors. A great deal of current research promises to help “unpeel” the many layers of this problematic “onion.” Examples of such new information are the observations of a reduction in the elasticity of resistance vessels in hypertension with aging21 and in diabetes mellitus.22 Such changes have long been demonstrated and their impact has been related directly to the occurrence of vascular events in such individuals. However, more subtle changes have also been observed that are less frequently recognized. While significant decreases in vascular elasticity are known in diabetics, when compared with those with normal carbohydrate tolerance, a less dramatic but significant decrease in vascular elasticity has been seen in those with impaired glucose tolerance,22 implying that the vascular changes that typically accompany diabetes mellitus are seen before the onset of overt diabetes. These findings emphasize the notion that the abnormalities associated with the arbitrary definitions of “diabetes,”“hypertension,”“obesity,”“dyslipidemia,” and related disorders are just the tip of the iceberg and that a continuous relationship exists between these measures and clinical events, as has been demonstrated most readily for BP. Until recently, the practicing physician focused on compartmentalized abnormalities such as those noted above. Treatment was started when threshold levels of BP, glucose, and lipids were reached without careful consideration of the additive risk resulting from the concomitance of more than a single abnormality. However, the emerging concept that the risk of these individual measures is continuous and that the thresholds established are arbitrary and in many cases outdated (i.e., 140/90 mm Hg based on actuarial data collected between 1929–1959 when life expectancy was markedly lower than it is today) combined with the elucidation that many of these factors are interrelated and frequently coexist, demands increased consideration of multiple factors and the impact of treatment approaches on them. For example, some treatments for hypertension such as β-adrenergic–blocking drugs have the potential to worsen insulin sensitivity, producing diabetes in some individuals, and to raise triglycerides and lower high-density lipoproteins. Thus, it now becomes necessary to evaluate patients for multiple abnormalities when one of these components is found and to consider therapeutic approaches that have the potential to remedy the underlying cause, or perhaps to address more than one problem, rather than to improve one problem while worsening another. The new therapeutic modalities on the horizon may offer such opportunities.